tbuckley/cabot-search huggingface dataset:
Immune checkpoint inhibitors-associated periodontitis: A propensity score-matched retrospective cohort study.
Authors: Yuanping Hsia, Cho Hsien Chiang, Cho Han Chiang, Cho Hung Chiang, Cheng-Ming Peng, Her-Shyong Shiah, Kevin Sheng-Kai Ma
Journal: Journal of Clinical Oncology (2023)

e14618 Background: Immune checkpoint inhibitors (ICIs) have been associated with a wide spectrum of immune-related adverse events (irAE) including oral mucositis and xerostomia. Periodontitis is another form of common oral pathology characterized by severe gingival inflammation but has not been investigated in patients receiving ICIs. We aimed to evaluate the risk of periodontitis associated with the use of ICI and to determine the clinical outcome of ICI-associated periodontitis. Methods: We conducted a 1:1 propensity score-matched retrospective cohort study involving patients receiving ICIs between January 2010 and November 2021. The primary outcome was periodontitis and the secondary outcomes were overall survival (OS), progression-free survival (PFS), and objective response rates. The propensity score matching was performed using basic demographics, underlying comorbidities, cancer type, and cancer therapy. The risk of periodontitis and associations between periodontitis and survival were evaluated using Cox proportional hazard analysis and Kaplan-Meier survival analysis. Results: We matched 868 patients receiving ICIs to patients who did not receive ICIs. Among ICI users, 41 (4.7%) patients developed periodontitis. The incidence rate of periodontitis was about 2-fold higher in ICI users than non-users (55.3 vs 25.8 per 100 patient-years; incidence rate ratio: 2.1 [95% CI: 1.4-3.3], p &lt; 0.001). In Cox regression analyses, the use of ICI was associated with an 80-90% increased risk of periodontitis. The presence of immune-related periodontitis was associated with improved OS (median not reached vs. 17.8 months, p &lt; 0.001), PFS (median 14.9 vs. 5.6 months, p = 0.009), and objective response rates (complete or partial response, 55% vs. 27%, p &lt; 0.001). In Cox regression analyses, ICI use was associated with a 30-60% lower risk of all-cause mortality or disease progression. Conclusions: ICIs were associated with an increased risk of periodontitis. ICI-related periodontitis was associated with better survival outcomes and treatment responses.[Table: see text]
Prognostic value of human leukocyte antigen G (HLA-G) expression in solid tumors: A systematic review and meta-analysis.
Authors: Jorge Bartolome, Consolacion Molto, Javier David Benitez Fuentes, Gonzalo Fernández-Hinojal, Aránzazu Manzano, Pedro Perez Segura, Abhenil Mittal, Faris Tamimi, Eitan Amir, Alberto Ocana
Journal: Journal of Clinical Oncology (2023)

e14639 Background: Identification of modulators of the immune response with inhibitory properties that could be susceptible for therapeutic intervention is a key goal in cancer research. An example is the human leukocyte antigen G (HLA-G), a nonclassical major histocompatibility complex (MHC) class I molecule, involved in cancer progression. Methods: We performed a systematic review and meta-analysis on the role of HLA-G expression and outcome in solid tumors. A total of 25 studies met the inclusion criteria comprising data from 4871 patients reporting overall survival (OS) outcomes, and 961 patients, in 5 studies, for disease free survival (DFS). This study was performed in accordance with PRISMA guidelines and registered in PROSPERO. Results: HLA-G expression was associated with worse OS (HR 2.09, 95% CI = 1.67 to 2.63; P &lt; .001), that was higher in gastric (HR = 3.40; 95% CI = 1.64 to 7.03), pancreatic (HR = 1.72; 95% CI = 0.79 to 3.74) and colorectal (HR = 1.55; 95% CI = 1.16 to 2.07) cancer. No significant differences were observed between the most commonly utilized antibody (4H84) and other methods of detection. HLA-G expression was associated with DFS which approached but did not meet statistical significance. Conclusions: We describe the first meta-analysis associating HLA-G expression and worse survival in a variety of solid tumors.
Lenvatinib in combination with PD-1 inhibitor and hepatic arterial infusion chemotherapy (HAIC) for patients with potentially resectable hepatocellular carcinoma: A retrospective analysis.
Authors: Wei Dong, Songyan Zhang, Zhuoni Huo, Junrong Lu, Haishi Liu, Ping Wang, Yubao Zhang
Journal: Journal of Clinical Oncology (2023)

e16160 Background: Surgical resection is the primary radical treatment for hepatocellular carcinoma (HCC). However, the percentage of initially resectable HCC is only 15-30%, and most patients are unable to undergo surgical resection at the time of initial diagnosis. Lenvatinib combined with PD-1 inhibitor and transarterial intervention has demonstrated good efficacy and safety in unresectable HCC. The retrospective study was designed to explore the safety and conversion effects of lenvatinib + camrelizumab+ HAIC in potentially resectable HCC. Methods: In this single-arm retrospective study, investigators collected patients with potentially resectable HCC treated with lenvatinib + camrelizumab + HAIC from November 2020 to December 2022. The potentially resectable population was selected by the following screening criteria: acceptable liver function (Child-Pugh A-B), good ECOG PS (0-1), intrahepatic tumors confined to one lobe (left, right, or middle lobe), and unresectable by surgical or oncological causes. Results: A total of 64 patients with potentially resectable HCC were included in this analysis. The conversion rate was 31.25% (20), and 23.4% (15) patients underwent surgery. The ORR and DCR were 56.3% and 85.9% by RECIST 1.1. Progression had occurred in 8 patients by the data cutoff on November 1, 2022. The median follow-up time was 13.6 months (range: 2.9-23.7) and 8 patients died. The data was not yet mature, with 1-year survival rate of 90.7%, Overall, 65.6% of patients experienced at least one treatment emergent adverse event (TEAE) and 15.6% of patients had Grade 3/4 TEAE, the most common was hand and foot syndrome (7.8%, n=5). Conclusions: Lenvatinib combined with PD-1 inhibitor and HAIC was well tolerated and showed potential conversion efficacy in the treatment of patients with potentially resectable HCC.
Long-term survival with IDH wildtype glioblastoma: First results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium (EORTC 1419).
Authors: Michael Weller, Joerg Felsberg, Dorothee Gramatzki, Emilie Le Rhun, Jennifer Leigh Clarke, Riccardo Soffietti, Wolfgang Wick, Olivier L. Chinot, Francois Ducray, Patrick Roth, Peter Hau, Martin Klein, Matthias Preusser, Martin Bendszus, Vassilis Golfinopoulos, Andreas von Deimling, Thierry Gorlia, Patrick Y. Wen, Guido Reifenberger, Caroline Hertler
Journal: Journal of Clinical Oncology (2023)

2016 Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and by the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumors, prognostic factors were analyzed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. Results: At the cut-off of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 not otherwise specified) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumors with O 6 -methylguanine DNA methyltransferase ( MGMT) promoter methylation. Median overall survival was 9.9 years (95% CI 7.9–11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p&lt;0.001) and had a high rate of MGMT promoter unmethylated tumors. Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Never relapsing patients often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma. Clinical trial information: NCT03770468 .
Heterogeneous baseline immune cell infiltration landscape as a predictor of pathological complete response in locally advanced esophageal squamous cell carcinoma (ESCC) following neoadjuvant chemotherapy and immunotherapy: Results from a single-arm, phase II clinical trial (SEEK-01).
Authors: Guangyu Yao, Renfeng Wang, Zhiliang Huang, Chaoxiang Du, Borong Chen, Zhenyang Lin, Tao Zhang, Zhonghua Wu, Hong Fan
Journal: Journal of Clinical Oncology (2023)

4047 Background: Neoadjuvant immunotherapy and chemotherapy have shown promise in improving outcomes for patients with locally advanced ESCC, but the response to treatment can vary among patients. Therefore, there is a need to identify predictive biomarkers that can guide treatment decisions and improve patient outcomes. The infiltration of immune cells within the tumor microenvironment has been shown to be an important factor in cancer progression and response to treatment. In this study, we sought to explore the immune microenvironment prospectively related to treatment response of Neoadjuvant immunotherapy by scRNAseq. Methods: This was a single-arm phase II clinical trial, planned to enroll 20 locally advanced ESCC patients (cT2-4N0-1M0). After neoadjuvant chemotherapy (paclitaxel-albumin + carboplatin) combined with tislelizumab, patients received minimal invasive esophagectomy (MIE).Prior to neoadjuvant therapy, fresh tumor tissues were obtained via endoscopy and used for scRNAseq analysis, to evaluate the predictive capacity of the immune microenvironment. Pathological outcomes were assessed and divided into pCR, MPR defined as &lt;10% residual tumor excluding pCR, and non-MPR defined as &gt;10%. Results: Out of 18 enrolled patients, 15 completed neoadjuvant therapy and MIE surgery since March 2022. Of these 15 patients, 3 achieved pCR, 2 got MPR, and 10 were non-MPR, with a total of 51,208 single cells sequenced. Both groups showed similarly low expression of PD-L1 (5.7% vs. 2.3%). Comparing pCR to non-MPR patients, the former showed a significant increase in T lymphocytes (CD8+(17.1% vs.1.1%), Regulatory T(20.2% vs.4.0%)), plasma cell(22.0% vs.8.3%), and mature dendritic cell(1.5% vs.0.5%); a significant decrease in B cells(0.9% vs. 1.9%), neutrophils(1.7% vs.11.0%), and tumor cell, as well as a similar expression of macrophage(5.6% vs.6.6%) and monocyte, indicating a clear difference in the immune cell infiltration landscape between two groups. Furthermore, we identified a new subtype of plasma cell which was highly enriched in the non-MPR group, even though the pCR group showed a great increase in plasma cells in total. Conclusions: This study demonstrates the heterogeneity of baseline immune cell infiltration landscape in Locally Advanced ESCC, in which pCR and non-MPR patients exhibited entirely different profiles, and provide a potential predictor of response to neoadjuvant immunotherapy. Our findings suggest that baseline immune cell infiltration status, rather than pd-L1 expression, could accurately predict pCR or non-MPR before treatment, which could guide personalizing and minimize the need for trial-and-error approaches.
A phase 1/2 study of retifanlimab (INCMGA00012, Anti–PD-1), INCAGN02385 (Anti–LAG-3), and INCAGN02390 (Anti–TIM-3) combination therapy in patients (Pts) with advanced solid tumors.
Authors: Omid Hamid, Martin Gutierrez, Inderjit Mehmi, Monika Dudzisz-Sledz, Paul Edward Hoyle, Wendy Wei, John D. Powderly
Journal: Journal of Clinical Oncology (2023)

2599 Background: In cancer treatment (tx), loss of T-cell function is associated with progressive expression of checkpoint (CP) molecules, and resistance or relapse following PD-(L)1 inhibitor therapy is a high unmet need. LAG-3 and TIM-3 are key CP pathways implicated in resistance to PD-1 inhibitors and have shown synergistic effects upon triple inhibition with PD-1 in a murine model. This open-label, nonrandomized phase 1/2 study (NCT04370704) aims to determine optimal doses and preliminary safety and efficacy for the monoclonal antibody combinations of INCAGN02385, INCAGN02390, and retifanlimab. Here we report initial safety and efficacy results. Methods: Study consists of 4 parts in phase 1 and 2 expansion cohorts in phase 2. In phase 1, parts 1 and 2 determined safety of INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W and INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W + retifanlimab 500 mg Q4W, respectively; parts 3 and 4 will test additional dosing schedules. Pts enrolled had previously treated (including PD-[L]1) locally advanced unresectable or metastatic solid tumors, with no prior LAG-3– or TIM-3–directed therapy. Results: As of June 28, 2021, 21 pts were enrolled in parts 1 (n=10) and 2 (n=11); 62% of pts were &lt;65 years and 38% were male. Pts had median 3 (range 1-9) prior lines of therapy, including prior anti–PD-(L)1 (part 1, 8 pts; part 2, 11 pts); pt tumor types are listed. Nineteen pts discontinued tx, 1 due to toxicity. Nine pts in part 1 and 10 pts in part 2 had tx-emergent adverse events (TEAEs), most commonly anemia and diarrhea (each 30%) in part 1 and anemia (36%) in part 2 (all tx-unrelated). Serious tx-related TEAEs occurred in 1 pt in part 1 (grade [G] 3 vasculitis) and 1 pt in part 2 (G3 myocarditis and pericardial effusion). Most common G≥3 TEAE was G3 anemia (part 1, 2 pts; part 2, 3 pts); 1 pt in part 1 had a G5 TEAE of sepsis unrelated to tx, with COVID-19 infection. In part 2, 1 pt had an infusion-related reaction, and 1 pt had immune-related TEAEs of pericardial effusion and myocarditis (both G3 and tx-related), which resolved after steroid therapy and tx discontinuation. Best overall response in part 1 was stable disease, and in part 2 was a confirmed and durable partial response in 1 pt with CP therapy–refractory melanoma. Conclusions: Doublet anti–LAG-3 + anti–TIM-3 and triplet anti–LAG-3 + anti–TIM-3 + retifanlimab regimens in the study were generally well tolerated in heavily pretreated pts, with a safety profile consistent with that of CP monotherapy and no novel toxicities. Optimal doses of both combinations are to be further evaluated in the ongoing study in first-line tx of melanoma. Clinical trial information: NCT04370704 . [Table: see text]
VHH-based chimeric antigen receptor T cells against CD70 to eliminate primary and re-challenge renal cell carcinoma tumors in preclinical study.
Authors: Pengfei Jiang, Qinghui Xiong, Haiying Wang, Tian Deng
Journal: Journal of Clinical Oncology (2023)

e14540 Background: CD70 is not expressed in normal tissue, but highly expressed on various hematopoietic and solid tumors, including renal cell carcinoma (RCC). It is an ideal target for cancer therapy and recently was proved by good results in clinical trials of CD70 monoclonal antibody. Methods: We obtained 4 VHH antibody（2A5, 8B4, 11C9 and 9D8）against CD70 by screen nanobody library derived from an antigen-immunized alpaca. Generated a panel of CAR-T cells by transduce retrovirus expressing CAR (chimeric antigen receptor) to human T cells isolated from health donors. These CAR constructs include 4 VHH sequences and a human scFv containing VH and VL derived from cusatuzumab. We evaluated CAR-T cell function in vitro included cell phenotype, proliferation, cytotoxicity, and cytokine release. Furthermore, RCC tumor cell-xenograft NOG mice models were used to test the anti-tumor activity of CAR-T cells in vivo. Results: All anti-CD70 CAR-T cells eliminate CD70-positive tumor cells but not CD70-negative cells in vitro. Although there were no significant differences between the killing efficiency of the CAR-T cells, more abundant IL-2 production in two VHH-based CAR-T cells (11C9 and 2A5) were observed in multi-round co-culture assay. CAR-T cells eradicated RCC tumor cell in our Xenograft model. After infusion, human T cells expanded over 250 folds in 11C9 group and over 30 folds in 2A5 group, but only nearly 6 folds in human scFv CAR-T treated group. In our second in vivo experiment, all mice treated with higher dose CAR-T, the VHH groups maintained tumor free statue much longer time than human scFv group. Cured mice were re-challenged by subcutaneously infuse RCC tumor cells, observed and measured tumor in the next 53 days. For 11C9 CAR-T treated group, 3of 7 mice maintained tumor-free, 1 of 7 mice were tumor-palpable but too small to measurement; For 2A5 treated group only 1 of 7 mice maintained tumor-free. A significantly greater expansion of human T cells in 11C9 group but not 2A5 group after re-challenge. Conclusions: Our results indicate a promising VHH-based CD70 CAR-T cells for RCC therapy, supporting further development for future clinical trial and application.
The immune microenvironment in hormone positive, HER2 negative breast cancer: A focus on tumour infiltrating lymphocytes, spatial phenotypes and tertiary lymphoid structures.
Authors: Mairi Lucas, Zak Kinsella, Claudia Aura Gonzalez, Camille Hurley, Anthony O'Grady, Joanna Fay, Verena Murphy, Chowdhury Arif Jahangir, Arman Rahman, William M. Gallagher, Catherine Margaret Kelly, Darran O'Connor
Journal: Journal of Clinical Oncology (2023)

2522 Background: Hormone positive, HER 2 negative breast cancer (ER+/HER2-) has traditionally been considered an immune cold tumour subtype. Research to date indicates that TILs in ER+/HER2- breast cancer may be a negative prognostic marker. However, there is a paucity of data in this area regarding immune subpopulations and spatial phenotypes. Tertiary lymphoid structures (TLS) have been associated with improved prognosis and response to immunotherapy in other solid organ malignancies. We aim to explore the immune microenvironment in early stage ER+/HER2- breast cancer with a focus on tumour infiltrating lymphocytes, spatial phenotypes and tertiary lymphoid structures (TLS). Methods: Full face sections of archival tissue samples from patients with early stage ER+/HER2- breast cancer were stained with CD45 antibody (DAKA clone M0701) via the automated Leica Bond III system. Open source digital pathology analysis software, Qupath, was utilised to identify positive cells and calculate the percentage of positive CD45 staining cells (CD45%) within the tumour area. Spatial analysis was done to divide tumour area into three spatial phenotypes; Immune cold -lacking immune infiltrate;Immune excluded- immune cells restricted to the tumour periphery and immune hot - immune cells infiltrating the tumour core. A tissue micro array (TMA) was created and stained manually with a multiplex chromogenic immunohistochemistry panel for CD20/CD3/DCLamp to identify immune subpopulations associated with tertiary lymphoid structures. Results: A total of 409 patient samples were included in the analysis. 89% (n=367) of samples had a CD45% of 0-10%. CD45% stratification by 21-gene-recurrence score(RS) into Low, Intermediate and High showed a statistically higher CD45% in those with a High RS compared to Low RS (p value= 0.0015). We identified a trend towards worse disease free survival (DFS) in the CD45%high group which did not reach statistical significance. The immune hot spatial phenotype was associated with a worse DFS (p value = 0.034) with no statistically significant difference in DFS between immune cold and immune excluded phenotypes. The majority of samples had minimal immune infiltrate. Staining with a TLS panel revealed that samples with a significant infiltrate could broadly be divided into T cell only infiltrate or those with the presence of TLS, the significance of this is unclear. Conclusions: The majority of ER+/HER2- breast cancer samples had low numbers of TILs, however there is clear heterogeneity within this subgroup. Spatial elements and immune cell subpopulations may further guide the value of TILs in prognosis in this breast cancer subtype.
Evaluation of immunotherapy response score (IRS) for predicting pembrolizumab (pembro) clinical benefit in patients (pts) with advanced solid tumors.
Authors: Sachdev P. Thomas, Ninah Achacoso, Chen Jiang, Elaine Chung, Aleyda V. Solorzano-Pinto, Pamela Tse, Benjamin J. Bulen, Nickolay A. Khazanov, Laura Elaine Lamb, Daniel H. Hovelston, Kat Kwiatkowski, D. Bryan Johnson, Daniel R. Rhodes, Scott A. Tomlins, Jennifer Marie Suga, Laurel A. Habel
Journal: Journal of Clinical Oncology (2023)

e14646 Background: IRS is a multivariable biomarker algorithm combining tissue-based tumor mutation burden (TMB) with quantitative gene expression biomarkers, previously validated to predict anti-PD-1 and anti-PD-L1 monotherapy (mono) benefit in an observational clinical trial (PMID: 36750617). Herein, we evaluated IRS in pts with advanced solid tumors across the Kaiser Permanente Northern California (KPNC) health system following a pre-specified statistical analysis plan. Methods: KPNC pts with valid IRS results (from 2018 – 2022; specimen collection years 2011-2021) and electronic health record (EHR) documented &gt; 1 st line systemic pembro mono treatment were included; pts with gliomas or previous immunotherapy were excluded. All oncologic treatments were obtained from the EHR and standardized to determine time to next treatment (TTNT) as a real-world progression free survival endpoint. A within-pt evaluation was performed, comparing pembro TTNT to the pt’s immediate prior therapy line (prior) TTNT. The primary objective was to determine if IRS status (-H vs. Low [-L]) predicts pembro clinical benefit in Cox proportional hazards models through testing for interaction between IRS status and pembro/prior therapy TTNT. Results: With a data cutoff of 06/15/2022, 211 KPNC pts (142 2 nd line and 69 &gt; 2 nd line pembro) were eligible and included (from 24 solid tumor types). The median (m) pembro follow-up was 16.0 months. IRS-H pts (n = 77, 36%) had significantly longer pembro vs. prior TTNT (mTTNT 20.3 mo vs. 4.5 mo, log-rank p-value &lt; 0.0001), whereas IRS-L pts (n = 134, 64%) did not (mTTNT 3.3 mo vs. 5.2 mo, log-rank p-value 0.75); the interaction between IRS status and pembro/prior treatment was significant (interaction test p-value &lt; 0.0001). Conclusions: IRS predicted pan-solid tumor pembro mono benefit compared to prior therapy and may be a potential marker for pembro mono treatment decisions. Clinical trial information: NCT03061305 .